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- EMDB-54127: Human alpha1 Na+,K+-ATPase in the Na+-occluded E2P state -

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Basic information

Entry
Database: EMDB / ID: EMD-54127
TitleHuman alpha1 Na+,K+-ATPase in the Na+-occluded E2P state
Map datamain map, 3SD
Sample
  • Complex: Na+,K+-ATPase alpha1/beta1/FXYD1
    • Protein or peptide: Sodium/potassium-transporting ATPase subunit alpha-1
    • Protein or peptide: Sodium/potassium-transporting ATPase subunit beta-1
    • Protein or peptide: Phospholemman
Keywordsactive ion transport / P-type ATPase / Na/K-ATPase / E2P / MEMBRANE PROTEIN / METAL TRANSPORT
Function / homology
Function and homology information


negative regulation of protein glutathionylation / protein transport into plasma membrane raft / Na+/K+-exchanging ATPase / regulation of cardiac muscle cell membrane potential / positive regulation of sodium ion export across plasma membrane / positive regulation of potassium ion import across plasma membrane / photoreceptor inner segment membrane / sodium ion binding / membrane repolarization during cardiac muscle cell action potential / P-type sodium:potassium-exchanging transporter activity ...negative regulation of protein glutathionylation / protein transport into plasma membrane raft / Na+/K+-exchanging ATPase / regulation of cardiac muscle cell membrane potential / positive regulation of sodium ion export across plasma membrane / positive regulation of potassium ion import across plasma membrane / photoreceptor inner segment membrane / sodium ion binding / membrane repolarization during cardiac muscle cell action potential / P-type sodium:potassium-exchanging transporter activity / steroid hormone binding / sodium:potassium-exchanging ATPase complex / regulation of calcium ion transmembrane transport / membrane repolarization / establishment or maintenance of transmembrane electrochemical gradient / sodium ion export across plasma membrane / cell communication by electrical coupling involved in cardiac conduction / intracellular sodium ion homeostasis / cardiac muscle cell action potential involved in contraction / response to glycoside / osmosensory signaling pathway / relaxation of cardiac muscle / regulation of heart contraction / regulation of cardiac muscle contraction by calcium ion signaling / Basigin interactions / cellular response to steroid hormone stimulus / chloride transport / organelle membrane / regulation of sodium ion transport / chloride channel activity / ATPase activator activity / potassium ion binding / phosphatase activity / potassium ion import across plasma membrane / intracellular potassium ion homeostasis / sodium channel regulator activity / Ion transport by P-type ATPases / intercalated disc / lateral plasma membrane / transporter activator activity / sperm flagellum / cardiac muscle contraction / ATP metabolic process / Ion homeostasis / proton transmembrane transport / muscle contraction / T-tubule / potassium ion transmembrane transport / protein localization to plasma membrane / sodium ion transmembrane transport / sarcolemma / caveola / intracellular calcium ion homeostasis / regulation of gene expression / melanosome / MHC class II protein complex binding / ATPase binding / protein-folding chaperone binding / extracellular vesicle / response to hypoxia / Potential therapeutics for SARS / basolateral plasma membrane / transmembrane transporter binding / protein-macromolecule adaptor activity / protein stabilization / apical plasma membrane / postsynaptic density / membrane raft / protein heterodimerization activity / axon / lysosomal membrane / protein kinase binding / Golgi apparatus / endoplasmic reticulum / ATP hydrolysis activity / protein-containing complex / extracellular exosome / ATP binding / membrane / plasma membrane
Similarity search - Function
: / Ion-transport regulator, FXYD motif / : / ATP1G1/PLM/MAT8 family / FXYD family signature. / Sodium and potassium ATPases beta subunits signature 2. / Sodium/potassium-transporting ATPase subunit beta / Sodium/potassium-transporting ATPase subunit beta superfamily / Sodium / potassium ATPase beta chain / Sodium and potassium ATPases beta subunits signature 1. ...: / Ion-transport regulator, FXYD motif / : / ATP1G1/PLM/MAT8 family / FXYD family signature. / Sodium and potassium ATPases beta subunits signature 2. / Sodium/potassium-transporting ATPase subunit beta / Sodium/potassium-transporting ATPase subunit beta superfamily / Sodium / potassium ATPase beta chain / Sodium and potassium ATPases beta subunits signature 1. / : / P-type ATPase subfamily IIC, subunit alpha / Cation-transporting P-type ATPase, C-terminal / Cation transporting ATPase, C-terminus / Cation transporter/ATPase, N-terminus / Cation-transporting P-type ATPase, N-terminal / Cation transporter/ATPase, N-terminus / P-type ATPase, cytoplasmic domain N / : / P-type ATPase actuator domain / P-type ATPase, haloacid dehalogenase domain / P-type ATPase, phosphorylation site / P-type ATPase, cytoplasmic domain N / E1-E2 ATPases phosphorylation site. / P-type ATPase, A domain superfamily / P-type ATPase / P-type ATPase, transmembrane domain superfamily / HAD superfamily / HAD-like superfamily
Similarity search - Domain/homology
Phospholemman / Sodium/potassium-transporting ATPase subunit alpha-1 / Sodium/potassium-transporting ATPase subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.24 Å
AuthorsChristensen ME / Habeck M / Katz A / Fruergaard MU / Karlish SJD / Nissen P
Funding supportEuropean Union, Denmark, 5 items
OrganizationGrant numberCountry
H2020 Marie Curie Actions of the European Commission793086European Union
LundbeckfondenR310-2018-3713 Denmark
Novo Nordisk FoundationNNF20OC0060483 Denmark
The Carlsberg FoundationCF22-1535 Denmark
The Carlsberg FoundationCF23-1394 Denmark
CitationJournal: Nat Commun / Year: 2026
Title: Active conformations of neuronal Na, K-ATPase isoforms and a disease-causing mutant.
Authors: Mads Eskesen Christensen / Michael Habeck / Adriana Katz / Marlene Uglebjerg Fruergaard / Yoav Peleg / Uri Pick / Steven J D Karlish / Poul Nissen /
Abstract: Na,K-ATPases establish and maintain the vital electrochemical gradients for Na and K across animal cell membranes. The protein is a ternary complex composed of α, β and FXYD subunits, of which ...Na,K-ATPases establish and maintain the vital electrochemical gradients for Na and K across animal cell membranes. The protein is a ternary complex composed of α, β and FXYD subunits, of which isoforms that fine-tune transport properties are expressed in a tissue-specific fashion. Here we report cryo-EM structures under active ATPase turn-over conditions of the ubiquitously expressed human α1β1FXYD1 and neuron-specific α3β1FXYD1 isoform complexes and probe their specific functional and biophysical properties. The data provides an extensive insight into Na-transport of ATP-activated enzyme through four distinct conformational states, including a sodium-bound phosphoenzyme intermediate, denoted [Na]E2P. This conformation reveals a crucial structural change that precedes Na release in the inward to outward (E1P-E2P) transition, within the general context of the sequential, active transport mechanism. We discuss the mechanism of the physiologically important differentiation in Na affinity of α3 compared to α1, the co-operative Na binding at the ion-binding sites, and the mechanistic aspects of cytoplasmic ion gating and extracellular Na release. Finally we present the structures of a disease-causing mutant form of α3, associated with Alternating Hemiplegia of Childhood (Q140L). The mutation compromises a specific phospholipid-binding pocket and impedes polyunsaturated phospholipid-mediated stimulation of Na,K-ATPase activity.
History
DepositionJun 20, 2025-
Header (metadata) releaseAug 12, 2026-
Map releaseAug 12, 2026-
UpdateSep 9, 2026-
Current statusSep 9, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_54127.png

Downloads & links

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Map

FileDownload / File: emd_54127.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmain map, 3SD
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.224 Å		0.83 Å/pix.
x 256 pix.
= 212.224 Å		0.83 Å/pix.
x 256 pix.
= 212.224 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.829 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0386
Minimum - Maximum-0.16666743 - 0.36572978
Average (Standard dev.)0.001019742 (±0.012867857)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.224 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Sharp map, 3SD

Fileemd_54127_additional_1.map
AnnotationSharp map, 3SD
Projections & Slices
AxesZYX

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Half map: half map A, 3SD

Fileemd_54127_half_map_1.map
Annotationhalf map A, 3SD
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B, 3SD

Fileemd_54127_half_map_2.map
Annotationhalf map B, 3SD
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

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Sample components

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Entire : Na+,K+-ATPase alpha1/beta1/FXYD1

EntireName: Na+,K+-ATPase alpha1/beta1/FXYD1
Components
  • Complex: Na+,K+-ATPase alpha1/beta1/FXYD1
    • Protein or peptide: Sodium/potassium-transporting ATPase subunit alpha-1
    • Protein or peptide: Sodium/potassium-transporting ATPase subunit beta-1
    • Protein or peptide: Phospholemman

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Supramolecule #1: Na+,K+-ATPase alpha1/beta1/FXYD1

SupramoleculeName: Na+,K+-ATPase alpha1/beta1/FXYD1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sodium/potassium-transporting ATPase subunit alpha-1

MacromoleculeName: Sodium/potassium-transporting ATPase subunit alpha-1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: Na+/K+-exchanging ATPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 113.012828 KDa
Recombinant expressionOrganism: Komagataella pastoris (fungus)
SequenceString: MGKGVGRDKY EPAAVSEQGD KKGKKGKKDR DMDELKKEVS MDDHKLSLDE LHRKYGTDLS RGLTSARAAE ILARDGPNAL TPPPTTPEW IKFCRQLFGG FSMLLWIGAI LCFLAYSIQA ATEEEPQNDN LYLGVVLSAV VIITGCFSYY QEAKSSKIME S FKNMVPQQ ...String:
MGKGVGRDKY EPAAVSEQGD KKGKKGKKDR DMDELKKEVS MDDHKLSLDE LHRKYGTDLS RGLTSARAAE ILARDGPNAL TPPPTTPEW IKFCRQLFGG FSMLLWIGAI LCFLAYSIQA ATEEEPQNDN LYLGVVLSAV VIITGCFSYY QEAKSSKIME S FKNMVPQQ ALVIRNGEKM SINAEEVVVG DLVEVKGGDR IPADLRIISA NGCKVDNSSL TGESEPQTRS PDFTNENPLE TR NIAFFST NCVEGTARGI VVYTGDRTVM GRIATLASGL EGGQTPIAAE IEHFIHIITG VAVFLGVSFF ILSLILEYTW LEA VIFLIG IIVANVPEGL LATVTVCLTL TAKRMARKNC LVKNLEAVET LGSTSTICSD KTGTLTQNRM TVAHMWFDNQ IHEA DTTEN QSGVSFDKTS ATWLALSRIA GLCNRAVFQA NQENLPILKR AVAGDASESA LLKCIELCCG SVKEMRERYA KIVEI PFNS TNKYQLSIHK NPNTSEPQHL LVMKGAPERI LDRCSSILLH GKEQPLDEEL KDAFQNAYLE LGGLGERVLG FCHLFL PDE QFPEGFQFDT DDVNFPIDNL CFVGLISMID PPRAAVPDAV GKCRSAGIKV IMVTGDHPIT AKAIAKGVGI ISEGNET VE DIAARLNIPV SQVNPRDAKA CVVHGSDLKD MTSEQLDDIL KYHTEIVFAR TSPQQKLIIV EGCQRQGAIV AVTGDGVN D SPALKKADIG VAMGIAGSDV SKQAADMILL DDNFASIVTG VEEGRLIFDN LKKSIAYTLT SNIPEITPFL IFIIANIPL PLGTVTILCI DLGTDMVPAI SLAYEQAESD IMKRQPRNPK TDKLVNERLI SMAYGQIGMI QALGGFFTYF VILAENGFLP IHLLGLRVD WDDRWINDVE DSYGQQWTYE QRKIVEFTCH TAFFVSIVVV QWADLVICKT RRNSVFQQGM KNKILIFGLF E ETALAAFL SYCPGMGVAL RMYPLKPTWW FCAFPYSLLI FVYDEVRKLI IRRRPGGWVE KETYY

UniProtKB: Sodium/potassium-transporting ATPase subunit alpha-1

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Macromolecule #2: Sodium/potassium-transporting ATPase subunit beta-1

MacromoleculeName: Sodium/potassium-transporting ATPase subunit beta-1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.232566 KDa
Recombinant expressionOrganism: Komagataella pastoris (fungus)
SequenceString: MARSHHHHHH HHHHPRRSRG KAKEEGSWKK FIWNSEKKEF LGRTGGSWFK ILLFYVIFYG CLAGIFIGTI QVMLLTISEF KPTYQDRVA PPGLTQIPQI QKTEISFRPN DPKSYEAYVL NIVRFLEKYK DSAQRDDMIF EDCGDVPSEP KERGDFNHER G ERKVCRFK ...String:
MARSHHHHHH HHHHPRRSRG KAKEEGSWKK FIWNSEKKEF LGRTGGSWFK ILLFYVIFYG CLAGIFIGTI QVMLLTISEF KPTYQDRVA PPGLTQIPQI QKTEISFRPN DPKSYEAYVL NIVRFLEKYK DSAQRDDMIF EDCGDVPSEP KERGDFNHER G ERKVCRFK LEWLGNCSGL NDETYGYKEG KPCIIIKLNR VLGFKPKPPK NESLETYPVM KYNPNVLPVQ CTGKRDEDKD KV GNVEYFG LGNSPGFPLQ YYPYYGKLLQ PKYLQPLLAV QFTNLTMDTE IRIECKAYGE NIGYSEKDRF QGRFDVKIEV KS

UniProtKB: Sodium/potassium-transporting ATPase subunit beta-1

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Macromolecule #3: Phospholemman

MacromoleculeName: Phospholemman / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.754979 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GTKAESPKEH DPFTYDYQSL QIGGLVIAGI LFILGILIVL SRRCRCKFNQ QQRTGEPDEE EGTFRSSIRR LSTRRR

UniProtKB: Phospholemman

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.5 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMC7H15NO4S3-(Morpholin-4-yl)propane-1-sulfonic acid
150.0 mMNaClsodium chloride
3.0 mMMgCl2magnesium chloride
1.0 mMC10H16N5O13P3Adenosine 5-triphosphate
0.015 mg/mlC47H88O22Lauryl maltose neopentyl glycol
GridModel: C-flat-1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 20 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.88 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

3wgu


Details: 3WGU was used for transmembrane domain of alpha1, beta1 and FXYD1. 4HYT for cytoplasmic domains of alpha1
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 84156
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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